The role of professional and non-professional antigen presenting cells in peripheral T cell tolerance and autoimmunity

Immunological tolerance to self is essential in the prevention of autoimmune disease. The two main types of DCs, conventional DC (cDCs) and plasmacytoid DC (pDCs), are involved in peripheral tolerance induction. Recently, LN resident radio-resistant cells, the LN stromal cells (LNSCs), have been suggested to contribute to peripheral T cell tolerance. Here we show that LNSCs contribute to CD4+ T cell tolerance via the acquisition of peptide-MHCII complexes from DCs. Moreover, we also explored a therapeutic role for pDCs in a mouse model of Multiple Sclerosis, the experimental autoimmune encephalomyelitis (EAE). Adoptive transfer of pDCs into C57BL/6 mice after EAE onset induced significant inhibition of EAE clinical symptoms. The elucidation of the cellular and molecular mechanisms involved in pDC-mediated EAE inhibition could shed light into an important therapeutic role for pDCs in MS. In conclusion, my work unraveled some important cellular and molecular mechanisms that underpin the tolerizing roles of Ag presentation by new cell types, from both the hematopoietic and the nonhematopoietic origins

VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics

Tumor expression of the lymphangiogenic factor VEGF-C is correlated with metastasis and poor prognosis, and although VEGF-C enhances transport to the draining lymph node (dLN) and antigen exposure to the adaptive immune system, its role in tumor immunity remains unexplored. Here, we demonstrate that VEGF-C promotes immune tolerance in murine melanoma. In B16 F10 melanomas expressing a foreign antigen (OVA), VEGF-C protected tumors against preexisting antitumor immunity and promoted local deletion of OVA-specific CD8(+) T cells. Naive OVA-specific CD8(+) T cells, transferred into tumor-bearing mice, were dysfunctionally activated and apoptotic. Lymphatic endothelial cells (LECs) in dLNs cross-presented OVA, and naive LECs scavenge and cross-present OVA in vitro. Cross-presenting LECs drove the proliferation and apoptosis of OVA-specific CD8(+) T cells ex vivo. Our findings introduce a tumor-promoting role for lymphatics in the tumor and dLN and suggest that lymphatic endothelium in the local microenvironment may be a target for immunomodulation

Immune cell landscaping reveals a protective role for Tregs during kidney injury and fibrosis

Acute kidney injury (AKI) and chronic kidney diseases (CKD) are associated with high mortality and morbidity in hospitalized patients. Although the underlying mechanisms determining the transition from acute to irreversible chronic injury are not well understood, immune mediated inflammatory processes are critical in renal injury. We have performed a comparison of two mouse models leading to either kidney regeneration or fibrosis, to better characterize the cellular and molecular events leading to both outcomes. Global gene expression profiling and histological analysis revealed a major upregulation of immune system related pathways during fibrosis. Further unbiased examination of the immune cell composition, using single-cell RNA sequencing, revealed that tissue resident macrophages and T cells were major altered populations. In fibrotic kidneys, there was a marked increase in tissue resident IL33R+ and IL2Ra+ regulatory T cells (Tregs). Indeed, prophylactic expansion of this population resulted in protection from kidney injury and fibrosis. Transcriptional profiling of Tregs showed a differential up-regulation of regenerative and pro-angiogenic set of genes in the regeneration model, whereas they expressed markers of hyper activation and fibrosis in the fibrosis model. This suggests that Tregs could exert different functions in the same tissue, dictated by environmental cues. Overall, we have provided a detailed cellular and molecular characterization of murine kidneys after injury and identified key changes in immune cell populations during fibrosis development

Lymphatic endothelial cells prime naïve CD8+ T cells into memory cells under steady-state conditions

Lymphatic endothelial cells (LECs) chemoattract naïve T cells and promote their survival in the lymph nodes, and can cross-present antigens to naïve CD8+ T cells to drive their proliferation despite lacking key costimulatory molecules. However, the functional consequence of LEC priming of CD8+ T cells is unknown. Here, we show that while many proliferating LEC-educated T cells enter early apoptosis, the remainders comprise a long-lived memory subset, with transcriptional, metabolic, and phenotypic features of central memory and stem cell-like memory T cells. In vivo, these memory cells preferentially home to lymph nodes and display rapid proliferation and effector differentiation following memory recall, and can protect mice against a subsequent bacterial infection. These findings introduce a new immunomodulatory role for LECs in directly generating a memory-like subset of quiescent yet antigen-experienced CD8+ T cells that are long-lived and can rapidly differentiate into effector cells upon inflammatory antigenic challenge

Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fibrosis

Acute kidney injury (AKI) and chronic kidney diseases are associated with high mortality and morbidity. Although the underlying mechanisms determining the transition from acute to chronic injury are not completely understood, immune-mediated processes are critical in renal injury. We have performed a comparison of 2 mouse models leading to either kidney regeneration or fibrosis. Using global gene expression profiling we could identify immune-related pathways accounting for the majority of the observed transcriptional changes during fibrosis. Unbiased examination of the immune cell composition, using single-cell RNA sequencing, revealed major changes in tissue-resident macrophages and T cells. Following injury, there was a marked increase in tissue-resident IL-33R+ and IL-2Ra+ regulatory T cells (Tregs). Expansion of this population before injury protected the kidney from injury and fibrosis. Transcriptional profiling of Tregs showed a differential upregulation of regenerative and proangiogenic pathways during regeneration, whereas in the fibrotic environment they expressed markers of hyperactivation and fibrosis. Our data point to a hitherto underappreciated plasticity in Treg function within the same tissue, dictated by environmental cues. Overall, we provide a detailed cellular and molecular characterization of the immunological changes during kidney injury, regeneration, and fibrosis

Peptides containing T cell epitopes, derived from Sm14, but not from paramyosin, induce a Th1 type of immune response, reduction in liver pathology and partial protection against Schistosoma mansoni infection in mice

Sm14 and paramyosin are two major Schistosoma mansoni vaccine candidate antigens. Recently, we have identified Sm14 and paramyosin epitopes that are recognized by T cells of resistant individuals living in endemic areas for schistosomiasis. Herein, mice were immunized with these peptides separately or in association in order to evaluate their vaccine potential. Immunization of mice with Sm14 peptides alone or mixed with paramyosin peptides was able to induce 26%-36.7% or 28%-29.2% of worm burden reduction, 67% or 46% of intestinal eggs reduction and also 54%-61% or 43%-52% of liver pathology reduction, respectively. Protection was associated with a Th1 type of immune response induced by Sm14 peptide immunization. In contrast, paramyosin peptide vaccination did not engender protective immunity or liver pathology reduction and immunization was associated with a Th2 type of immune response. (C) 2008 Elsevier B.V. All rights reserved

Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes

Evidence has recently emerged that butyrophilins, which are members of the extended B7 family of co-stimulatory molecules, have diverse functions in the immune system. We found that the human and mouse genes encoding butyrophilin-2A2 (BTN2A2) are regulated by the class II trans-activator and regulatory factor X, two transcription factors dedicated to major histocompatibility complex class II expression, suggesting a role in T cell immunity. To address this, we generated Btn2a2-deficient mice. Btn2a2(-/-) mice exhibited enhanced effector CD4(+) and CD8(+) T cell responses, impaired CD4(+) regulatory T cell induction, potentiated antitumor responses, and exacerbated experimental autoimmune encephalomyelitis. Altered immune responses were attributed to Btn2a2 deficiency in antigen-presenting cells rather than T cells or nonhematopoietic cells. These results provide the first genetic evidence that BTN2A2 is a co-inhibitory molecule that modulates T cell-mediated immunity